Flexible and scalable sensor arrays for recording and modulating physiological activity

ABSTRACT

An implantable sensor array incorporates active electronic elements to greatly increase the number of sensors and their density that can be simultaneously recorded and activated. The sensors can be of various configurations and types, for example: optical, chemical, temperature, pressure or other sensors including effectors for applying signals to surrounding tissues. The sensors/effectors are arranged on a flexible and stretchable substrate with incorporated active components that allow the effective size, configuration, number and pattern of sensors/effectors to be dynamically changed, as needed, through a wired or wireless means of communication. Active processing allows many channels to be combined either through analog or digital means such that the number of wires exiting the array can be substantially reduced compared to the number of sensors/effectors on the array.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a Continuation of U.S. patent applicationSer. No. 14/795,745 filed Jul. 9, 2015, which is a Divisional of U.S.patent application Ser. No. 12/921,808, filed Nov. 12, 2010, now U.S.Pat. No. 9,107,592 issued Aug. 18, 2015, which claims priority toInternational Patent Application No. PCT/US2009/036956 filed Mar. 12,2009, which in turn claims benefit of U.S. Provisional Application No.61/035,909 filed Mar. 12, 2008.

FIELD OF THE INVENTION

The present invention relates to a biological sensor/effector (e.g.stimulation) array that is manufactured using flexible and stretchableactive electronics so as to better conform to the natural shape of thebrain, peripheral and cranial nerves, heart, blood vessels, spinal cordand other biological structures, and have a higher density of sensorsthan is possible with current electrode array technology. Theintegration of active electronics also allows for dynamicsensor/effector reconfigurability for scalable sensing and integratedpatterned stimulation.

BACKGROUND OF THE INVENTION

There is a great need for flexible, multi-scale, configurablesensor/effector systems that can be cut to specific sizes and shapes andadapted “on the fly” to adjust to specific temporal and spatialrecording scales in the body. A driving motivation for such technologyis the rapidly growing awareness that brain, cardiac and otherbiological recordings must be made multi-scale, spanning from individualand multiple unit (cell) activities to large-scale field potentials,depending upon the application. These sensor systems must also becapable of both recording and modulating tissue function, as part of newdiagnostic and therapeutic devices for neurological and other diseases,brain and other tissue injury, and acquired conditions.

Taking an example from the brain-computer interface technologies, thecurrent state of the art for flexible subdural grid electrodes forlocalizing seizures in the human brain typically utilize ˜4 mmplatinum-iridium or stainless steel contacts spatially separated by 10mm.

Such electrodes are available from Ad-Tech Medical InstrumentCorporation (http://www.adtechmedical.com). As illustrated in FIG. 1, along-term monitoring (LTM) subdural grid 10 of this type containing 16contacts 20 has a separation of 10 mm between each contact 20, and 1 or2 “tails” 30 that contain contacts 40 for output of electrical signalsthat correspond to each contact 20 on the subdural grid (each contact 20on the subdural grid has an individual wire attached to it, which isconnected to a contact 40 in one of the “tails.”) Similar electrodes areillustrated in U.S. Pat. No. 4,735,208, entitled “Subdural stripelectrodes for determining epileptogenic foci.” However, theseelectrodes are not effective for detecting all signals of interest inthe brain, for example, due to their large size and large spacingbetween contacts.

The choice of the particular sizing and spacing of the electrodes ispartly based upon clinical tradition and partly based on technologicallimitations of the design, such as requiring that each contact has awire dedicated to conducting its signals to the recording apparatus.Studies on neocortical neuron density suggest that there areapproximately 12 million neurons contained within the square centimeterof neocortex sampled by each one of these electrodes (See Pakkenberg B &Gundersen H J. Neocortical neuron number in humans: effect of sex andage. J Comp Neurol (1997) 384: pp. 312-320). It seems very unlikely thatthis would be a sufficient spatial sampling to capture even a smallamount of the information available from this type of recording. Theexact resolution for sensing and modulating activity in brain,peripheral nerve, spinal cord or other tissues in the body depends uponthe particular application (e.g. brain-computer interface, functionalelectrical stimulation, alleviation of pain, etc.). A single electrodesystem that has the capability to resolve a broad range of theseactivities, tunable to a particular task, would be highly desirable anduseful. In addition, being able to configure dimensions of the recordingsurface, through a broad range of configurations (e.g. to interface witha particular gyms, dorsal root entry zone, peripheral or cranial nervebundle) would be highly desirable, and contribute to great economy inpower use, computational burden and minimize disruption of normaltissues.

In addition, the actual tissue contact region of the electrode systemneeds to be “changeable,” as different applications may requirerecording from either the surface of tissues, from contacts thatpenetrate tissues to be close to particular types of cells, nuclei,nerve bundles or specific tissues, or perhaps from a combination oradjustable array of contact types. The proposed system is designedspecifically with this type of flexibility in mind, allowing the“business end” of the system, the portion of the system that actuallycontacts biological tissues, to be adaptable and changeable in manydifferent combinations.

To achieve the desired range of spatial sampling for signals of interestalong with the desired area of coverage, it is clear that the number ofsensor/effector contacts must be on the order of thousands, not tens oreven hundreds, and that the spatial resolution of these sensor/effectorcontacts must be “scalable,” (e.g. their effective size and spacing beadjustable without having to physically move or alter them). As anexample, since each contact of existing brain/subdural electrode systemsis either individually wired and assembled (e.g. Ad-Tech systems) orfabricated such that individual wires output signals from each contact(e.g. Utah array), it is clear that a more integrated design thatincorporates multiplexing control techniques is needed to minimize thenumber of leads required and to make production feasible and costeffective. This also provides a safety advantage over currentintracranial electrode systems, as there is evidence that the number of“tails” or leads extruding from the body can be related directly tomorbidity in the case of subdural grids for brain recording, forexample.

In the case of subdural electrodes for monitoring brain activity, otherelectrode designs have attempted to overcome the problem of spatialundersampling by making the electrodes smaller and more closely spaced.For example, the Utah Electrode Array 50 shown in FIG. 2 has an array ofcontacts spaced 0.4 mm apart. The Utah Electrode Array is described byNordhausen C T, Maynard E M & Normann R A in “Single unit recordingcapabilities of a 100 microelectrode array,” Brain Res. (1996), Vol.726, pp. 129-140. While this provides a more desirable density ofelectrodes, the overall area of cortex that is sampled by the electrodearray 50 is only 4 mm×4 mm, due to the small array size of 10×10contacts. This amount of spatial coverage is insufficient for mostclinical applications. Extending this electrode design to a larger arraysize is difficult because each electrode must be individually wired andbecause the array is made from inflexible silicon that does not conformto the shape of the tissues.

Several improvements have been suggested to fix the first problem ofwiring complexity. Two such examples are illustrated in FIGS. 3 and 4.The example of FIG. 3 is described by Patterson W, Yoon-Kyu Song, BullC, Ozden I, Deangellis A, Lay C, McKay J, Nurmikko A, Donoghue J &Connors B. in “A microelectrode/microelectronic hybrid device for brainimplantable neuroprosthesis applications,” IEEE Transactions onBiomedical Engineering (2004), Vol. 51, pp. 1845-1853, while the exampleof FIG. 4 is described by Aziz J, Genov R, Bardakjian B, Derchansky M &Carlen P. in “256-channel integrated neural interface andspatio-temporal signal processor, Circuits and Systems, 2006. ISCAS2006. Proceedings. 2006 IEEE International Symposium on (2006), p. 4. Inthese electrode circuit designs, each electrode is connected to its ownamplifier cell 60 (inset, FIG. 4). As shown in FIG. 4, each cell 60includes a programmable high pass filter 61 and low pass filter 62,preamp 63, final amp 64, a sample-and-hold circuit 65, and an analogmemory 66. In this way, each electrode can have its own dedicatedamplifier and programmable filter bank. The outputs of all of theamplifier cells 60 in a given column are multiplexed together using anarray of analog switches 70, and rows are multiplexed using an analogmultiplexer 80 to allow all of the electrode outputs to be reduced to asingle time-division multiplexed output line 85. This technique greatlyreduces the number of wires that must exit the electrode array. However,the inflexible silicon substrate that these circuits are fabricated onstill limits their use to sampling a small area of brain tissue wherethe surface can be approximately flat.

An ideal sensor/effector array would be flexible and stretchable toallow it to conform to the round and contoured surface (and within sulciand other recesses) of the brain or other biological tissues. Someattempts have been made to fabricate implantable electrodes usingflexible printed circuit technology. For example, FIG. 5 illustrates theimplantable electrodes 90 described in U.S. Pat. No. 6,024,702. However,this technique only allows for passive circuit elements, and so theproblem of wiring complexity still remains.

The present invention addresses these and other needs in the art.

SUMMARY OF THE INVENTION

The present invention simultaneously overcomes the challenges remainingin the prior art by providing vastly increased sensor/effector density,increased area of coverage, and decreased wiring complexity throughelectrode multiplexing. By reducing the volume and complexity ofintracranial wiring, and the volume of the implantable device, theproposed sensor array should also reduce morbidity and complicationsresulting from sensor implantation. Those skilled in the art will alsoreadily appreciate that a sufficiently thin and flexible electrodearray, such as that described, will allow for novel implantationtechniques. These include, but are not limited to, endoscopic proceduresand unfolding/unrolling sensor/effector arrays through a burr-hole, orintroduced into blood vessels (e.g. on stents etc.) and other hollowstructures via catheters. By enabling more minimally invasiveprocedures, the arrays of the invention can further reduce morbidity andmortality associated with sensor/effector implantation procedures. Thesesame advantages exist for applications to other biological systemsoutside of the brain, such as heart, kidneys, stomach, cranial nerves,and other regions.

The microelectrode array of the present invention is fabricated usingflexible and stretchable active electronics to overcome the difficultyin conforming to the surface of the brain and the geometry of otherbiological structures. Also, the array is designed in an extensiblemanner such that electrodes can be scaled up from micro to macro scaleas needed, and such that the sensing elements can be interchanged withvarious light, electrical, chemical, temperature or othermicrofabricated sensing elements, as well as different kinds ofelectrical contacts, such as those that sit on the surface of (as opposeto penetrating) tissue.

The method and associated apparatus of the invention address theabove-mentioned needs in the art by providing a high densitysensor/effector array, such as a cortical surface electrode array, thatis manufactured using flexible and stretchable active electronics so asto provide integrated multiplexed amplification and analog to digitalconversion on the array; dynamic electrode reconfigurability byproviding a grid of switches on the electrodes that switch based onnumber of contacts sampled, size of the electrodes, sampling rate, bitdepth, shape and sampling region; coalescence of micro electrodes intomacro electrodes; integrated patterned stimulation; wired or wirelessreal-time configuration and control; on-board closed-loop control; bloodvessel imaging, and functional brain imaging (as electrical contactscould be changed for optical sensors) including locating the vessels andcreating images; tracking of electrode position and migration; hardwareand software tools for collecting, analyzing and displayingmulti-channel, broadband neurophysiological or other biological signals;and providing digital data output using a high speed serial data bus.

An exemplary embodiment of the invention relates to an implantablecortical surface electrode array that incorporates active electronicand/or optical, chemical, or other sensor elements to greatly increasethe number of electrodes that can be simultaneously recorded from andstimulated (including optical or chemical stimulation). The electrodesare arranged in a 2-dimensional grid in a first embodiment of theinvention, but may be extended to a 3-dimensional grid, if penetratingelectrode elements are used. The array is constructed on a flexible andstretchable substrate with incorporated active components that allow theeffective size and number of contacts to be dynamically changed, asneeded, through a wired or wireless means of communication. Activeprocessing allows many channels to be combined either through analog ordigital means such that the number of wires exiting the electrode arraycan be substantially reduced compared to the number of electrodes on thearray. The individual electrodes are micro-scale and arranged in a highdensity array, but can be electrically connected through a series ofanalog switches to record as larger structures through activelogic/control elements. Acquired signals are multiplexed down to areduced set of wires or potentially converted from analog to digitalsignals directly on the electrode array.

In exemplary embodiments, the implantable cortical surface electrodearray comprises a flexible substrate, an array of electrodes arranged onthe substrate, and active electronic elements incorporated into theflexible substrate. The array of electrodes is ideally very small,whereby an array of at least 100×100 electrodes may be in an area nogreater than 36 cm². The active elements selectively connect respectiveelectrodes so as to enable the effective size, configuration and numberof electrodes to be dynamically changed. The active electronic elementsare flexible and/or stretchable, so as to better contact and conform tosmall changes in the brain surface (e.g. gyri, sulci, blood vessels,etc.) and include analog or digital switches between respectiveelectrodes that are responsive to logic for selectively opening orclosing to selectively connect the respective electrodes to each other.For example, a plurality of electrodes may be connected by the switchesto form a macroelectrode.

The active electronic elements may also include an amplifier and ananalog to digital converter for amplifying and digitizing signalsdetected by the electrodes. The active electronic elements may also beresponsive to configuration and control signals provided by wire orwirelessly to the electrode array from a local or remote processingdevice. The processor may be part of the active electronic elements fora closed loop implantable embodiment and, in such case, may includealgorithms that, for example, track the position of respectiveelectrodes, identify migration of the electrodes on top of the corticalsurface, and track electrode impedance and other measures of signalquality that can follow surrounding tissue reaction to the contacts(e.g. gliosis).

In an exemplary embodiment, the active electronic elements may comprisea buffer amplifier at each electrode and a set of multiplexing switchesarranged in rows and columns. In such an embodiment, an analog todigital converter may be provided that receives and converts the outputsof all electrodes to a digital serial data stream.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe embodiments of the present invention, will be better understood whenread in conjunction with the appended drawings. For the purpose ofillustrating the invention, there are shown in the drawings embodimentswhich are presently preferred. As should be understood, however, theinvention is not limited to the precise arrangements andinstrumentalities shown. In the drawings:

FIG. 1 illustrates a prior art flexible subdural grid electrode that iscapable of sampling over a large surface area, but has poor spatialresolution due to the large 10 mm spacing between electrodes.

FIG. 2 illustrates a prior art microelectrode system having contactsspaced 400 μm apart, but is only capable of sampling a very small areaof approximately 4 mm×4 mm.

FIG. 3 illustrates a prior art multiplexed analog electrode system forinflexible microelectrode arrays.

FIG. 4 illustrates another prior art multiplexed analog electrode systemfor inflexible microelectrode arrays.

FIG. 5 illustrates a prior art flexible printed circuit electrode arraythat suffers from the limitation of wiring complexity.

FIG. 6 illustrates an exemplary embodiment of the inventionincorporating a digital signal processor and the capability formicrostimulation that may be used in a closed-loop clinical device forrecording cerebral activity and stimulating for diagnostic ortherapeutic purposes.

FIG. 7 illustrates an exemplary embodiment of the analog switchesutilized in FIG. 6.

FIG. 8 illustrates an exemplary embodiment of the circuit shown in FIG.6.

FIG. 9 illustrates an alternate electrode multiplexing technology basedon a CMOS digital imaging circuit.

FIG. 10 illustrates how different types of sensors (e.g., opticaldetectors, or chemical, temperature, pressure or other measurementdevices) can be designed into the array of FIG. 6 in place of some orall of the electrodes.

FIG. 11 illustrates how adjacent electrodes in a micro electrode arrayare interconnected by a series of analog switches, different from thosein FIG. 7, to allow the effective size and spacing of the electrodes tobe adjusted on the fly.

FIG. 12 illustrates one possible embodiment of the analog switchesutilized in FIG. 11 where the analog switch is coupled to a static RAMcell to maintain the switch state (open or closed) without interventionby the system logic.

FIG. 13 illustrates the resulting effective circuit when 4×4 groups ofelectrodes are combined by selectively closing the multiplexing analogswitches in the array.

FIG. 14 illustrates a possible fabrication technique that can beutilized to make the circuits of FIGS. 6, 8 and 9 flexible andstretchable.

FIG. 15 illustrates a second technique for fabricating the electrodearray of the invention.

FIG. 16 illustrates a third technique for fabricating the electrodearray of the invention.

FIG. 17 illustrates a fourth technique for fabricating the electrodearray of the invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

A detailed description of illustrative embodiments of the presentinvention will now be described with reference to FIGS. 1-17. Althoughthis description provides a detailed example of possible implementationsof the present invention, it should be noted that these details areintended to be exemplary and in no way delimit the scope of theinvention.

The following definitions will be used throughout this specification:

Sensor: Any element that can be used to transduce a biological signalinto an electrical or other signal. Examples of sensors include:electrical contacts for recording electrophysiological signals, opticaldetectors for recording light correlates of biological activity,chemical sensors for detecting changes in chemical concentrations or PH(e.g., chloride, neurotransmitters, lactate, glucose, other metabolites,neuro-active compounds, medications, biological substances such astumor-secreted factors, etc.), devices for measuring temperature, force,acceleration, movement, pressure, etc.

Effector: Any device that takes a signal and introduces an interventionto modulate biological (e.g., brain) activity. Examples of effectorsinclude electrical stimulators, photo/light-emitters (e.g., foractivating brain tissues impregnated with a light responsive compound),chemical releasing/infusion devices, devices that change temperature,pressure, and/or acceleration, and devices that introduce electrical,magnetic or other fields, etc. Illumination sources such as a lightsource or other source that can activate tissue for diagnostic ormonitoring purposes may also be used. For example, such illuminationsources may be used to activate brain tissue to interrogate its functionbut not necessarily to modulate its activity.

In the following specification, the term “sensor” will be understood toalso include functionality of the effector as defined above.

While exemplary embodiments of the invention are described herein in thecontext of a system of intracranial electrodes to record from andstimulate the brain, those skilled in the art will appreciate that theinvention may also be used as a configurable sensor and/or effector inthe following types of biological systems. The following list is notmeant to be exhaustive, but rather representative of the broad array ofmonitoring and modulation functions that can be subsumed by theinvention:

Cardiac sensors/effectors, such as for cardiac electrophysiologytesting, and devices such as pacemakers, defibrillators, electricallyactive catheters for going inside the heart and blood vessels, and thelike;

Neuroprostheses for special sensory organs, e.g. artificial retinas,cochlear implants, balance (vestibular and other cranial nerveinterfaces) prostheses, devices to aid in taste, smell, physicalsensation, proprioception, and other similar functions;

Neuroprostheses for recording and functional electrical stimulation ofmotor and other central and peripheral nerves for afferent and efferentfunctions (e.g. motor and sensation);

Implanted devices to go into tissues, such as intravascular and otherforms of sensor/effector covered stents for deployment in the brain orblood vessels;

Implantable devices for organ function monitoring, or monitoring oftissues for the presence or recurrence of tumors, cancer, metastases,etc.;

Implantable sheets of electrodes that can be wrapped around structuresfor patterned recording, stimulation or other functions, for example,pacing stomach or intestinal contractions to restore mobility toparalyzed tissues (e.g. due to diabetic gastroparesis); and

Endoscopic introduction into other cavities in the body, for example, inand around the heart, abdomen, inside organs, on muscular structuressuch as the bladder neck, inside blood vessels, on stents, etc.

Electrode Multiplexing

At the outset, the inventors recognize that to sample hundreds orthousands of electrodes simultaneously, a multiplexing strategy isdesired to reduce the number of wires that must come off of theelectrode array. Reducing the number of wires coming off of the array isalso advantageous because the number and size of leads implanted alongwith an electrode array has been found to correlate with risk ofinfection, brain swelling, and complications from implantation surgery.In addition, having electrode arrays with hundreds of connectionsgreatly increases the probability of operator error in making theconnections and properly setting up the labels on each channel.

Electrode array embodiments that embody exemplary multiplexingembodiments will be described in the following section.

Individually Buffered and Multiplexed Inputs

In an exemplary embodiment of the present invention, individual bufferamplifiers are incorporated at each electrode and their outputs aremultiplexed together. This design is illustrated in FIG. 6. Eachelectrode contact 100 is directly attached to a dedicated preamplifier110 that provides some gain to the signal and a low-output impedance todrive the column line 120. The output of the preamplifier 110 isconnected to the column line 120 through an analog switch 130.

The circuit details of the analog switch are shown in FIG. 7. The NMOSpass transistor 131 is driven by a digital logic signal, C, while thePMOS pass transistor 132 is driven by the output of the inverter 133. Inthis way, both pass transistors are active (conducting) when C is at ahigh logic level and both pass transistors are inactive (non-conducting)when C is at a low logic level. This allows analog signals to eitherpass through the device or not based on a digital logic control signal,C. Alternatively, FIG. 12 illustrates one possible embodiment of theanalog switches utilized in FIG. 11 where the analog switch 130 iscoupled to a static RAM cell 134 to maintain the switch state (open orclosed) without intervention by the system logic.

FIG. 6 shows columns of N electrodes 100, preamplifiers 110 and analogswitches 130. By activating a specific row signal 140 and de-activatingthe other N−1 row signals, the output of the selected row amplifier willbe allowed to drive the column line 120. In this manner, any one of theN rows can be selected to drive the column amplifier 150. This columnamplifier 150 provides additional gain to match the range of the signalto the input range of the column analog to digital converter 160. Thecolumn analog to digital converter 160 converts the analog signals fromthe electrode channels to digital values. The digital output of thecolumn analog to digital converter 160 is connected to a digital buffer170, and the outputs of all N digital buffers 170 (one for each column)are connected together. Each column signal 120 can be individuallyselected via the N column select signals 180. In this way, the data fromthe N column analog to digital converters 160 can be combined down toone digital input on the integrated microprocessor 190.

FIG. 8 illustrates one possible embodiment of the circuit shown in FIG.6. The circuit has been simplified to only show the amplifiers andanalog switches for 4 electrodes, arranged in a small grid of 2×2.However, FIG. 6 illustrates how this basic design can be extended to anynumber of rows and columns. In FIG. 8, the amplifier has beenimplemented using a source-follower architecture. In this configuration,three NMOS transistors 300 have been connected as a current source. Twoadditional NMOS transistors 310 and 320 are configured as a currentmirror and a final NMOS transistor 330 forms the active load. These sixtransistors comprise the amplifier (110 in FIG. 6). The output of thisamplifier is connected to a multiplexing transistor 340 (130 in FIG. 6)which serves to selectively enable the output of that amplifier.

Modified CMOS Image Sensor Structure

In an alternate embodiment of the invention, a CMOS digital image sensorhas been modified to multiplex the electrodes 100. As illustrated inFIG. 9, such a modified CMOS image sensor 200 includes an array ofelectrodes 100 that are connected to output amplifier 210 and addressedby suitable addressing circuitry 250. In an exemplary embodiment, ananalog to digital converter 225 may be connected to the output of outputamplifier 210 so as to provide A/D conversion on the image sensor array200. Correlated double sampling may be removed to prevent inadvertentstimulation of the cortex during the reset operation. Furthermodifications may be required to reduce the noise floor of the imagesensor array 200.

The CMOS image sensor of FIG. 9 works as follows. Each microelectrode100 is connected to the gate of a field effect transistor 220 ofamplifier 230. This transistor 220 is connected to the common verticalbias transistor 240 by means of a horizontal row select transistor 250.In this way, one half of an amplifier is formed at each pixel and theother half is shared among all the pixels in a given column. Anothersimilar configuration allows a given column to be selected to drive theoutput amplifier 210. This high bandwidth amplifier 210 provides thegain required to match the detected EEG signals to the range of theanalog to digital converter 225 that samples the signal and outputs thedigital data over a single Low-Voltage Differential Signaling (LVDS)high speed serial data bus 260. For example, a commercially available10-bit, 20 MSPS analog-to-digital converter 225 may be used thatoperates using less than 50 mW so that it may be integrated onto theelectrode array 200 to provide an output bit stream for recording andstorage.

Modified CCD Structure

In another alternate embodiment, a CCD, or Charge Coupled Device, ismodified in its design to accept direct electrical input, instead oflight input. In this modality, the EEG signal creates packets of chargein the device that are transferred along the device, until ultimatelyread out.

Electrode Details

The flexible electrode arrays described above and illustrated in FIGS. 6and 9 include N² electrodes. These electrodes can be many possible typesof electrodes. For example, the electrodes 100 may be made of gold,platinum, platinum-iridium, tungsten or other substances includingconductive non-metals. The electrodes 100 may be in the shape of“bumps”, flat round or square patches, or small penetrating spikes.Other embodiments of the “tissue end” of this electrode system maypenetrate tissue (e.g. brain) using tetrodes, silicon and platinummicroelectrode arrays and silicon microprobes, among others.

Additionally, the electrodes 100 do not need to be electrodes at all.Some or all of the electrodes 100 may be replaced with other solid-statesensors that can be designed to output an electrical signal. Forexample, FIG. 10 shows a variation of the circuit of FIG. 6 where someof the electrodes 100 have been replaced by photodiodes 270. With anappropriate illumination source, these light sensors 270 could be usedto measure local blood oxygen concentration, blood flow, or otherparameters. Other solid-state sensors that could be integrated onto thearray in place of one or more electrodes to measure local chemicalconcentrations, pH, temperature, force, magnetic field and more.

Electrode Coalescence

The analog switch 280 of FIG. 11 placed between adjacentmicro-electrodes 100 allows the creation of electrically connectedcontacts of arbitrary size. For example, if the following switches inthe example schematic are programmed as follows:

Active Inactive r0c0, r0c2 r0c1 r1c0, r1c1, r1c2, r1c3 r2c1 r2c0, r2c2r3c0, r3c1, r3c2, r3c3 r5c0, r5c1, r5c2, r5c3 r4c1 r6c0, r6c2 r6c1then the resulting effective circuit will be the circuit shown in FIG.13. The net result of this transformation is a 4× reduction in spatialsampling. This would allow a 4× increase in sampling rate or bit depthor a similar reduction in power consumption. Further spatial aggregationwould be possible as well, right up to or beyond the size of currentmacro electrodes. A dynamic algorithm could be employed that wouldintelligently combine and dissociate electrodes such that areas ofinterest could be automatically identified and spatially sampled at ahigher density while areas of less interest could be sampled at a lowerdensity. Furthermore, the sampling sites could be customized such thatareas that do not need to be sampled, like vasculature, could beignored. This might be done, for example, by taking a digital picture ofthe area to be recorded, or abstracting this from an MM image, and thenprogramming the electrode array to record only from those electrodes incontact with regions of interest, or to silence contacts positioned overelectrically inactive regions. It is important to note that being ableto customize sensor/stimulator size by aggregating a number ofelectrodes, may have distinct neurophysiological advantages based uponfeatures of the cortical or subcortical structure or network beingrecorded or stimulated. For example, if a group of contiguous corticalcolumns of a particular dimension is the basic functional unit thatneeds to be monitored or stimulated, this structure might best berecorded or stimulated with electrodes aggregated into groups of 4 or16, rather than single contacts. Similarly, if a single cortical columnneed be activated, this might be best done with single contacts, oraggregated contacts from a system in which the electrodes are moreclosely spaced.Stimulation

An additional overlay of demultiplexing logic plus a digital to analogconverter (160 of FIG. 6) can be added to the electrode array to allowmicro-stimulation at one or more contact sites. The intelligence mayalso be provided in an interface or a remote processing unit, asdesired. The stimulation for the electrodes may be pre-programmedpatterns developed to accomplish particular tasks, such as to modulateepileptiform activity, initiate or inhibit function, map blood vessels,and map functions of neural tissue. In other applications, stimulationmight be controlled in closed loop, via active software, based uponrecorded signals or using continuous feedback to modulate neuronalactivity for therapeutic purposes.

On-Board Closed Loop Control

An additional microprocessor or digital signal processor 190 can beadded to the electrode array of FIG. 6 to enable its use as astand-alone closed-loop control system. This system would incorporate asampling control system, signal processing, and a stimulation controlinto the microprocessor or digital signal processor 190 to allow theelectrode array to become a fully self-sufficient implantable device.The processor 190 may include algorithms to provide for vessel orfunctional brain imaging, location and recording, and to track theposition of respective electrodes and identify migration of theelectrodes 100 within cortical tissue. In order to conserve batterylife, the number of channels sampled can be reduced to only the channelsthat are of most interest and clinical value. The other amplifiers onthe array can be shut down or only sampled periodically to reduce powerconsumption and data processing requirements. This embodiment alsoallows for periodic updating of the electrodes used as networks evolveand function changes or migrates over time. Of course, hardware andsoftware tools may be implemented in conjunction with the electrodearrays described herein to collect, analyze, and display themulti-channel, broadband neurophysiological signals detected by theelectrode arrays of the invention.

Area

A conventional neural amplifier occupies 0.16 mm² of space using a veryconservative 1.5 um-CMOS process (Harrison R & Charles C., “A low-powerlow-noise CMOS amplifier for neural recording applications,” IEEEJournal of Solid-State Circuits, (2003) Vol. 38, pp. 958-965). Toachieve a 100×100 array in 36 cm², each amplifier must occupy less than0.36 mm² of space. This means that using a similar design wouldleave >55% of the surface area available for interconnects and otherlogic, which should make the design feasible.

Data Storage and Archiving

A 100×100 grid array will contain 10,000 electrodes. Sampling eachelectrode at 2000 Hz will yield a total sampling rate of 20 MSPS. At 12bits/sample, this yields 30 MB/s of data. This becomes 101 GB/hr and 2.4TB/day. However, a simple differential encoding scheme should be able toreduce this data set by at least a factor of 4. Considering that 1 TBsingle hard drives are currently available and that hard drive pricescontinue to fall, this amount of data seems large but manageable. Ifneeded, the data can be down-sampled and the recording can be adjustedto the task as required. For example, the patient could be recorded at asampling rate of 500 Hz per channel at rest and automatically adjustedto 2 KHz per channel synchronized with particular cognitive tasks orperiods of increased probability of seizure onset. Another strategywould be to collect data at the best quality all the time and thenutilize a background server task that compresses, prunes and archivesdata to be saved.

Interface

Once the data is converted from analog to digital, the samples need tobe transmitted to a computer for storage and analysis. This link needsto use as few wires as possible, while consuming little power andproviding a reasonable cable length, interference tolerance and room toexpand to larger array sizes. The use of an LVDS link (260 of FIG. 9)reduces the power consumption of the data transmission, reduces radiatedelectromagnetic noise and allows data transmission of up to 1 Gigabitper second and beyond over a single pair of wires. At the currentestimated data rate of 240 Mbps, several transmission techniques shouldbe capable of performing this task. Among them are USB 2.0, Firewire400/800, eSATA and Gigabit Ethernet. As an example, a USB 2.0 interfacechipset with integrated microprocessor (See Ez-usb Fx2lp™ usbmicrocontroller athttp://download.cypress.com.edgesuite.net/design_resources/datasheets/contents/cy7c68013a_8.pdf)consumes 165 mW of power while delivering up to 53 MB/s data transferrate. This should be sufficient for integration into a device. Iffurther power savings are required, a custom low-voltage differentialsignaling (LVDS) protocol can be designed that can attempt to bettermeet the needs presented by this electrode array.

Power

A calculation of the maximum allowable power consumption can beestimated from the simulations presented by Ibrahim T S, Abraham D &Rennaker R L in “Electromagnetic power absorption and temperaturechanges due to brain machine interface operation,” Ann Biomed Eng.,(2007) Vol. 35: pp. 825-834. The study concludes that 78 mW/cm² is anallowable power dissipation for a 1 degree Celsius temperature rise.Another work states that a heat flux of only 80 mW/cm² can cause tissuedamage (T M, Harasaki H, Saidel G M & Davies C R, “Characterization oftissue morphology, angiogenesis, and temperature in the adaptiveresponse of muscle tissue to chronic heating,” Lab Invest. (1998), Vol.78, pp. 1553-1562).

A current design low-power amplifier for neural recordings consumes 15μW per channel (Aziz J, Karakiewicz R, Genov R, Chiu A, Bardakjian B,Derchansky M & Carlen P., “In vitro epileptic seizure predictionmicrosystem,” Circuits and Systems, 2007, ISCAS 2007. IEEE InternationalSymposium on (2007), pp. 3115-3118). This means that a 10,000 channelelectrode array might consume 150 mW of power. If these 10,000 channelsare spread out over a 36 cm² electrode array, the threshold for damagemight be as high as 2.88 W. Therefore, 150 mW may be an acceptable levelof power consumption. To improve the safety of the device, solid statetemperature sensors could easily be integrated into the array to measurethermal rise. If an unsafe temperature rise is measured, the arraysampling rate can be turned down to reduce power. If this fails tocontrol the temperature rise, the array can be completely turned off.

Additionally, the power consumed by all the active elements on the arrayshould be considered as well. If the power consumed by the amplifiers,analog to digital converter(s), microprocessor and interface logic(Table 1) is added up, then the total power consumption of the array canbe estimated to be around 430 mW. This level of power consumption andassociated heat generation may be acceptable for implantation but testdata is required for safety evaluations of different tissues.

TABLE 1 Power budget breakdown Component Power 10,000 amplifiers  150 mWAnalog to digital conversion  65 mW Misc logic power  50 mWMicroprocessor and USB Interface  165 mW Total  650 mW Max Allowablepower in 36 cm² 2880 mW

The active elements on the array also may be powered by power inducedfrom sources outside of the body such as through inductive coupling fromRF coils, and the like, to permit remote activation, data transmission,etc. when needed or desired from the active elements, without requiringan integrated power source.

Fabrication Techniques

The electrode array of the invention may be manufactured using one of anumber of available fabrication techniques. For example, in accordancewith a first technique disclosed by J. Rogers at the University ofIllinois at Urbana-Champaign, buckled silicon nanoribbons have beenshown to provide a stretchable form of single-crystal silicon forhigh-performance electronics on rubber substrates (FIG. 14) (See Kyanget al. in “A Stretchable Form of Single-Crystal Silicon forHigh-Performance Electronics on Rubber Substrates,” Science, Vol. 311,13 Jan. 2006). J. Rogers has also shown that printed semiconductornanomaterials may be used to form heterogeneous three-dimensionalelectronics (See Choi W M, Song J, Khang D, Jiang H, Huang Y Y & RogersJ A, “Biaxially stretchable ‘wavy’ silicon nanomembranes,” Nano Lett.,(2007) Vol. 7, pp. 1655-1663.).

In the fabrication technique of FIG. 14, a stretchable single-crystal Sidevice is built on an elastomeric substrate. In the first step (top),thin (thicknesses between 20 and 320 nm) elements of single-crystal Sior complete integrated devices (transistors, diodes, etc.) arefabricated by conventional lithographic processing, followed by etchingof the top Si and SiO₂ layers of a SOI wafer. After these procedures,the ribbon structures are supported by, but not bonded to, theunderlying wafer. Contacting a prestrained elastomeric substrate (PDMS)to the ribbons leads to bonding between these materials (middle).Peeling back the PDMS, with the ribbons bonded on its surface, and thenreleasing the prestrain, causes the PDMS to relax back to its unstrainedstate. This relaxation leads to the spontaneous formation ofwell-controlled, highly periodic, stretchable wavy structures in theribbons (bottom).

Those skilled in the art will appreciate that the fabrication techniquesdisclosed by J. Rogers et al. is advantageous in that the devices andcircuits are fabricated on traditional silicon using standard SOI(silicon on insulator) processing techniques and in that very highperformance devices, on par with standard silicon devices, are produced.Moreover, simple transfer mechanisms yield well-defined wavy siliconstructures that are not only flexible, but stretchable as well. However,the development of 2-dimensional stretchable devices is in an earlystage and could be expensive since such devices require one entire waferof silicon per electrode array, including all of its traditional SOIprocessing steps, plus additional processing steps to make the siliconflexible.

Another method for fabricating the electrode arrays of the invention isprovided by using single-walled nanotubes (SWNTs) (FIG. 15). Asdescribed by J. Rogers at the University of Illinois at Urbana-Champaignin an article by Hong et al., “A Flexible Approach to Mobility,” NatureNanotechnology, Vol. 2, April 2007, such an approach has the potentialfor very high performance flexible devices as SWNTs have carriermobilities of ˜10,000 cm²/Vs, which is about 10× better than silicon.The performance of such single-walled nanotubes is described by Zhou etal. in “Band Structure, Phonon Scattering, and the Performance Limit ofSingle-Walled Carbon Nanotube Transistors,” P. Phys. Rev. Lett., Vol.95, 146805 (2005).

In the fabrication technique of FIG. 15, a flexible electronic device ismade by growing randomly orientated single-walled carbon nanotubes on anamorphous SiO2 surface (a) and then growing dense aligned nanotubes on aquartz crystalline surface (b). These steps are followed by the directtransfer of the nanotubes onto flexible substrates by flexible polymercoating (c) and removal of the quartz (d) to produce flexible,high-performance, high-power electronic devices. However, thistechnology is still in its early stages, and only single devices havebeen fabricated to date. Lithography techniques are needed to makecomplex circuits.

In accordance with another possible fabrication technique, thin goldfilms are provided on elastomeric silicone substrates to formstretchable microelectrode arrays (FIG. 16). Such an approach isdescribed by S. Wagner at Princeton in articles by Lacour S & Wagner S.entitled “Thin film transistor circuits integrated onto elastomericsubstrates for elastically stretchable electronics, Electron DevicesMeeting, 2005. IEDM Technical Digest. IEEE International (2005), pp.101-104, and by Tsay C, Lacour S, Wagner S & Morrison B. entitled“Architecture, fabrication, and properties of stretchablemicro-electrode arrays,” Sensors, 2005 IEEE (2005), pp. 1169-1172. Suchfabrication techniques are desirable as they have been demonstrated as aviable bio-compatible process for a stretchable micro-electrode.

In the fabrication technique of FIG. 16, an encapsulated electrode isformed on PDMS (FIG. 16a ). As shown in FIG. 16b , exposed metal issurrounded by encapsulated metal which is surrounded by encapsulatingPDMS. The exposed metal forms a contact in the clear encapsulationsilicone over the metal pad. However, the resulting active elements arerelatively slow and bulky. For example, a thin-film transistor (TFT)inverter only managed 500 Hz operation.

Finally, in accordance with yet another possible fabrication technique,surface-tree technology by laser annealing (SUFTLA) developed by EpsonCorporation may be used (FIG. 17). Such technology is described by Boydin “Epson Takes Major Step Toward Flexible Electronics,” TechnologyNewsline, No. 13, May 2005. As described in the Boyd article, such afabrication technique is a low cost, large surface area TFT processthrough which complex circuits have been successfully fabricated.However, this fabrication technique produces relatively low performancedevices with unpredictable propagation delays. Also, the resulting arrayis flexible, but not stretchable.

Implantation Techniques and Extensions

The implantable arrays described above may be deployed endoscopically orthrough some other means, such as through surgery (preferably minimallyinvasive). If the array is small, it may be implanted directly as aresult of its small footprint. On the other hand, the flexible substratemay be rolled up for introduction and unrolled, unfurled or otherwiseexpanded once inside the body. On the other hand, the flexible substratemay be placed into the body as part of a vascular stent deployablewithin the body or as an integral part of a catheter system that isplaced within vessels or organs, around peripheral or cranial nerves,and on, in or around other structures of the body.

Those skilled in the art also will readily appreciate that manyadditional modifications are possible in the exemplary embodimentwithout materially departing from the novel teachings and advantages ofthe invention. For example, a reshaped version of the disclosedelectrode arrays may be used to increase the spatial sampling of currentdepth implantable electrode designs as well. The circuits would bewrapped around the barrel of the electrode body, allowing amplificationand multiplexing throughout the length of the depth electrode. Thiswould greatly improve the number of microelectrodes that can be placedin deep brain structures, such as the hippocampus, amygdala, and theanterior nucleus of the thalamus. The array of sensors also may beformed into a hollow or solid cylindrical shape to be implanted into adeep brain structure, wrapped around a nerve bundle or auditory nerve, ablood vessel, a peripheral or cranial nerve, or provided outside orinside a viscus or in or around the heart or eye. On the other hand, thearray of electrodes may be formed into a device suitable for cardiacimplantation or for recording from and applying stimulation toperipheral or cranial nerves, a spinal cord, a heart, a viscus or otherbiological target in a patient. The sensor array also may be disposed ina chamber in which biological material removed from the body is placed,and the array or sensors in such an embodiment would record from ormonitor activity from the biological materials after removal from thebody. The sensor array could be powered via wires, batteries (single useor rechargeable), through wireless power (inductive coupling), or somecombination of those. Accordingly, any such modifications are intendedto be included within the scope of this invention as defined by thefollowing exemplary claims.

What is claimed is:
 1. An implantable cortical surface electrode array,comprising: a flexible substrate adapted for implantation in a tissue ofa patient and adapted to conform to a cortical surface; an array ofelectrodes arranged on said flexible substrate; and switchesincorporated into said flexible substrate, said switches arrangedbetween adjacent electrodes so as to selectively connect respectiveindividual electrodes to each other so as to enable effective size,configuration, and number of electrodes to be dynamically changed. 2.The implantable cortical surface electrode array of claim 1, whereinsaid switches comprise analog or digital switches arranged betweenadjacent electrodes, said switches being responsive to logic forselectively opening or closing said switches.
 3. The implantablecortical surface electrode array of claim 1, wherein said switches areflexible and/or stretchable.
 4. The implantable cortical surfaceelectrode array of claim 1, wherein said switches are responsive toconfiguration and control signals provided by wire or wirelessly to saidarray of electrodes.
 5. The implantable cortical surface electrode arrayof claim 4, further comprising a processor that provides saidconfiguration and control signals to said array of electrodes, whereinthe processor is incorporated into the flexible substrate.
 6. Theimplantable cortical surface electrode array of claim 5, wherein saidprocessor includes an algorithm that tracks a position of respectiveelectrodes and identifies migration of said electrodes within tissue. 7.The implantable cortical surface electrode array of claim 1, whereinsaid array of electrodes comprises at least 100×100 sensors in an areano greater than 36 cm².
 8. The implantable cortical surface electrodearray of claim 1, wherein said array of electrodes are formed to contactand conform to small changes in a brain surface.
 9. The implantablecortical surface electrode array of claim 1, wherein said array ofelectrodes are formed for neuroprostheses for recording and/orfunctional stimulation of motor and other central and peripheral nervesfor afferent and/or efferent bodily functions.
 10. The implantablecortical surface electrode array of claim 1, wherein said array ofelectrodes are formed into sheets for wrapping around structures forpatterned recording and/or stimulation.
 11. The implantable corticalsurface electrode array of claim 1, wherein said array of electrodesreceive power from at least one source outside of a patient's body. 12.The implantable cortical surface electrode array of claim 1, whereinsaid array of electrodes are arranged in a three-dimensionalconfiguration.
 13. The implantable cortical surface electrode array ofclaim 1, further comprising a buffer amplifier at each electrode and aset of multiplexing switches arranged in rows and columns, wherein thebuffer amplifier is incorporated into said flexible substrate.
 14. Theimplantable cortical surface electrode array of claim 1, wherein saidarray of electrodes further comprises sensors including one or moreelectronic sensors, optical sensors, chemical sensors, force sensors,and/or temperature sensors.
 15. The implantable cortical surfaceelectrode array of claim 1, wherein a plurality of electrodes areconnected by said switches to form a macrosensor.
 16. The implantablecortical surface electrode array of claim 14, further comprising anamplifier and an analog to digital converter incorporated into saidflexible substrate for amplifying and digitizing signals detected bysaid sensors.
 17. The implantable cortical surface electrode array ofclaim 14, further comprising an output amplifier that receives andamplifies the outputs of all sensors, wherein the output amplifier isincorporated into said flexible substrate.
 18. The implantable corticalsurface electrode array of claim 14, wherein said switches are arrangedto enable sampling from a large number of sensors simultaneously. 19.The implantable cortical surface electrode array of claim 1, whereinsaid array of electrodes further comprises effectors that applystimulation signals to the cortical surface when implanted, saideffectors including one or more electrical stimulators, illuminationdevices, chemical infusion devices, chemical release devices, heatingdevices, cooling devices, pressure devices, and magnetic field devices.20. The implantable cortical surface electrode array of claim 19,wherein a plurality of electrodes are connected by said switches to forma macroeffector.